Most of the film takes place inside the body of a slob, a widower named Frank (Bill Murray). The live-action sequences trace Frank’s illness: because of his unhealthy habits, he contracts a virus, develops an extremely high fever, and almost dies. After a miraculous recovery, he decides to follow the advice of his sensible daughter, Shane, and get more exercise, eat healthy food, and so on.

The rest of the film is animated, and tells the story of the illness from inside Frank’s body, a city with its own police force (the immune system, its precincts in the lymph nodes), organized crime (microbes who have a steambath in Frank’s armpit), the media (NNN, the Nerve Network News). The town is run from Cerebellum Hall by the corrupt Mayor Phlegmming, who discourages healthy eating habits because the huge number of fat cells vote for him. Chaos threatens with the arrival of Thrax (the voice of Laurence Fishburne), a virus who, as he puts it himself, "makes ebola look like dandruff."

The heroes are Osmosis Jones, a white blood cell (who is literally blue, and voiced by the black comedian Chris Rock), and Drix, a cold capsule (voice of David Hyde Pierce). Jones has been suspended for using "unnecessary force," by making Frank throw up in public (and in fact saving his life by expelling a toxic oyster), and Drix develops an inferiority complex when he realizes that he does not cure disease, but is only "for the temporary relief of symptoms." The two team up as vigilantes and, along with the attractive Leah, another immune cell who works as the Mayor’s Aid, they defeat Thrax and save the city.